In this competitive renewal, five principal investigators, who have a strong track record in making novel contributions to angiogenesis research, propose to continue their collaborative efforts which are focused on analysis of the molecular mechanisms responsible for control of normal and tumor angiogenesis and on identification of novel angiogenesis inhibitors. M. Klagsbrun, will analyze the function of neuropilins (VEGF and semaphorin receptors) and their ligands in a zebra- model of developmental angiogenesis and in mouse models of tumor angiogenesis and metastasis. D. lngber, will analyze the biomechanical mechanisms by which extracellular matrix acts locally to regulate capillary cell sensitivity to soluble angiogenic factors and thereby controls capillary morphogenesis. He will explore how local changes in matrix mechanics alter cytoskeleton tension generation and focal adhesion formation, how these alterations impact on cell migration and whether cell tension contributes to capillary pattern formation. P. D'Amore, has generated mice that express single VEGF isoforms (120, 164, and 188) and will analyze the role of VEGF isoforms in tumor angiogenesis and their interaction with neuropilin. Additionally, she will investigate the role of VEGF in the adult vasculature. M. Moses, will analyze the transcriptional regulation of VEGF expres-sion during the initiation of angiogenesis. She will also determine whether urinary MMPs alone, or in combination with VEGF and bFGF, can predict the initiation of angiogenesis during tumor progression. J. Folkman, will further explore the mechanisms of inhibitors to be used for antiangiogenic therapy. New goals include identification of novel specific inhibitors of lymphangiogenesis, determining whether circulating endothelial cell precursors are predictive of intense tumor angiogenesis and whether endometriosis, which has an invasive component, is angiogenesis-dependent and therefore a target of anti-angiogenesis therapy in patients. Together, the five research programs in this application cover a broad range of investigation that should significantly enhance our understanding of how angiogenesis is regulated and how it can be inhibited.